Proliferation Playing on Both Sides of the Field

John F. Foley

Science’s STKE, AAAS, Washington, DC 20005, USA

Signals from the T cell receptor (TCR) are important for activation, differentiation, and proliferation. Members of the B cell leukemia/lymphoma-2 (Bcl-2) family of proteins are critical regulators of T cell apoptosis. The proapoptotic members Bax (Bcl-2-associated X protein) and Bak (Bcl-2-antagonist/killer) prevent the accumulation of excess lymphocytes. Jones et al. investigated other roles for Bax and Bak in T cell physiology. The authors reconstituted irradiated recombination-activating gene-1 (RAG-1)-deficient mice, which are deficient in T cells, with bone marrow cells from Bax^–/–, Bak^–/– (DKO), or wild-type mice. TCR stimulation of DKO cells isolated from these chimeric mice resulted in defective activation and proliferation, as measured by flow cytometry and ³[H]-thymidine incorporation. Whereas TCR stimulation of DKO cells resulted in decreased concentration of intracellular Ca²⁺ ([Ca²⁺]_i) compared with that in wild-type cells, Western blotting analysis showed that phosphorylation of phospholipase C isoforms, which are downstream of TCR activation, was comparable in both cell types. Treatment of DKO CD4⁺ T cells with a cell-permeable inositol 1,4,5-trisphosphate (IP₃)-ester induced lower [Ca²⁺]_i than did treatment of wild-type cells, indicating that DKO cells have defective IP₃-dependent Ca²⁺ release from endoplasmic reticulum (ER) stores. This defect was reversed by either retroviral-mediated expression of Bax or treatment of DKO cells with ionomycin, which allows influx of extracellular Ca²⁺. DKO T cells were also defective for TCR-stimulated production of reactive oxygen species compared with wild-type cells. Together, these data establish Bax and Bak as important regulators of T cell proliferation through controlling TCR-stimulated Ca²⁺ mobilization from the ER.

R. G. Jones, T. Bui, C. White, M. Madesh, C. M. Krawczyk, T. Lindsten, B. J. Hawkins, S. Kubek, K. A. Frauwirth, Y. L. Wang, S. J. Conway, H. L. Roderick, M. D. Bootman, H. Shen, J. K. Foskett, C. B. Thompson, The proapoptotic factors Bax and Bak regulate T cell proliferation through control of endoplasmic reticulum Ca²⁺ homeostasis. Immunity 27, 268-280 (2007). [PubMed]